CDRH's Schultz Seeks More Postmarket Reports

Originally Published MDDI October 2004

WASHINGTON WRAP-UP

CDRH's Schultz Seeks More Postmarket Reports

The center's director prioritizes his effort to crack down on companies that fail to follow through with their postmarket reports.

James G. Dickinson

Journal Article Not Pulled to Please Medtronic | Utah Medical Protests FDA Lawsuit | Another TMJ Implants Inspection Beginst | AdvaMed Oposes FDA Policy on SUDs

CDRH's new director, Daniel P. Schultz, MD, has a full plate of priorities. Among them is his intention to fix the problem of device companies that don't follow through on commitments to conduct postmarket studies.

The fault is not the companies' alone, he acknowledged in an August interview—CDRH itself hasn't given the issue adequate attention. “We have not done a great job, and industry has done an even worse job,” he said.

Schultz explained that the majority of premarket approvals are issued with some postmarket monitoring or study requirements. The companies then report each year to FDA on their progress in meeting these requirements. But, for years, FDA has put a low priority on reviewing those annual reports. That's going to change.

The FDA Modernization Act established a need for the center to achieve a balance between pre- and postmarket product reviews, Schultz said. Previously, all its effort has been applied—with industry encouragement—to getting new products to market. Now he feels it's time to strike the required balance.

“I intend to work with the Office of Device Evaluation and the Office of Surveillance and Biometrics to try and do better there,” he told me.

Part of the reason that a balance has not been reached falls on CDRH. The center has failed to pay enough attention to designing appropriate postmarket studies and enforcing their accomplishment, according to Schultz. “Therefore, there is basically very little confidence among our premarket reviewers in saying, ‘We can study this and answer these questions postmarket.' In many cases, those questions never get answered. It's a vicious circle: if it's not done properly, everybody loses confidence. If we don't show that we're serious about it, then people don't see the reason for doing it. It's a downhill spiral, and I think there are ways we can reverse direction.”

Schultz also pointed out reasons why industry has failed in this area. FDA has, in the past, revoked product approvals because companies have failed to complete postmarket requirements. However, such actions have not motivated industry to complete the condition-of-approval postmarket studies. Schultz isn't suggesting that pulling products from the market for this reason is the way to achieve the required balance in pre- and postmarket FDA stringency. However, he is suggesting resources from user fees be used for the review and enforcement of postmarket study commitments in PMA sponsors' annual reports. Until now, he said, these report reviews have tended to fall to the bottom of the pile owing to the Office of Device Evaluation's premarket focus.

“If somebody says, ‘exactly how are you going to roll this initiative out?' I'm not sure I know how to answer that question yet. But we're working on it,” Schultz added.

On the center's list of priorities, Schultz ranked public health first. Since he graduated from the University of Pittsburgh medical school in 1975 and joined the Indian Health Service as a general practitioner, public health has also been his personal priority.

How will he accomplish that as center director? “Making sure MDUFMA succeeds is something that we absolutely have to do,” Schultz said. “Without those additional resources I think we will sink back towards where we were in the early 1990s in numbers of FTEs [full-time equivalent staff positions], where we would not have adequate resources to be able to review things quickly and at the same time make sure that we're doing it thoroughly. As a manager, that needs to be my highest priority—to make that happen.”

Schultz identified his second priority as “making sure that we have a strong scientific basis for our decisions, doing things in a risk-based way, and making sure that the center's goals are aligned with the agency's goals and the department's goals.”

His third priority is maintaining the center's own strategic goals. David Feigal, Schultz's predecessor, primarily publicized the idea of addressing the total product life cycle. Schultz acknowledged that this has not yet been fully attained across the center.

His fourth priority is working with the agency in its new “critical path” initiative. This initiative, defined by former commissioner Mark McClellan last January, involves applying scientific breakthroughs to improve people's health. In addition, it strives to make that path less costly and more certain.

Asked about the reported industry unrest because of the published 16% jump in user-fee levels for FY 2005, Schultz defended the center's figures. He said there had been many discussions with industry prior to those numbers being published in the Federal Register. “I understand that they aren't exactly what industry wanted,” he said, “but we were sensitive to their concerns. Some of those increases are based on how the statute was written.”

Schultz believes “things will level out” after the FY 2005 year. The user-fee program is vital to what he wants to do with the center. “I want to make it work. There are constraints, obviously, based on the way the legislation was written. I am hopeful that we can get through this hard period and get to the good stuff which is going to occur in the last couple of years, where we really have to start to meet some very, very challenging goals. I'd like to be able to demonstrate that, given the resources, we can meet those goals.”

Schultz said when MDUFMA was being negotiated, industry was adamant that fees be based solely on applications. “We knew that was going to be a problem,” Schultz reflected. Sure enough, after the act was in place, individual companies began adjusting their filing practices. They would reduce or combine submissions or convert from one type of submission to another. As a result, the numbers upon which the fee calculations were based “started to change—and I don't think there was any good way we could have predicted that.”

Schultz again emphasized that his goal “is not to make money. My goal here is to do what we need to do to serve the public. My only reason for wanting the user-fee program to succeed is not to have a bigger empire or to see CDRH get rich; it is to be able to do what we need to do in terms of public health.”

Journal Article Not Pulled to Please Medtronic

A scientific article that was recently pulled from the Journal of Vascular Surgery presented internal FDA processing and vetting concerns, according to Daniel Schultz. The article, written by FDA staff about Medtronic Inc.'s (Minneapolis) AneuRx stent graft system, raised concerns even though its data were already in the public domain, the CDRH director said in August. “The way in which the information was presented in the article was somewhat different from the way in which the information was presented in a previously issued public health notification,” he explained. “When I was asked to take a look at all of that together, I felt that the article needed to be pulled.”

The journal's editors didn't appreciate Schultz's intervention, complaining to news media that the agency “forced” them to pull the article. They also said that Medtronic officials, who complained that the article's authors had used confidential data in preparing it, provoked the intervention.

At issue were data related to a Phase 2 study of Medtronic's AneuRx stent graft system. On FDA's Web site in December 2003, the agency posted a public health notification. It included updated data on mortality associated with the Medtronic AVE AneuRx stent graft system. The article submitted to the journal was based on that notification.

The editors said they complied with Schultz's request. Afterward, they compared the data in the article with those in the notification and found they were identical. “In these documents, FDA analyzed aneurysm-related deaths in 942 patients from the Phase 2 trial who received the flexible AneuRx graft currently marketed,” the editors said.

“They reported a one-month postimplant death rate of 1.5% and thereafter an annualized aneurysm-related mortality rate of 0.4% per year. They estimated the cumulative aneurysm-related mortality to be 2.7% at three years after implant. Furthermore, FDA concluded that the risk of late aneurysm-related mortality associated with the AneuRx stent graft system may exceed that associated with open surgery in some institutions, and that the overall aneurysm-associated mortality from the AneuRx stent graft is likely to cross over and exceed the aneurysm-related mortality from open surgery at some point in time. They encouraged surgeons to carefully consider risk factors, including the risk of subsequent events, when recommending open versus endovascular repair.”

The journal editors said that objection to the article's publication could not be attributed to use of confidential data, since the data are already available on the FDA Web site. Furthermore, they said, FDA's explanation that the conclusions in the article go beyond the public health notification cannot apply to the data, which were identical. Rather, the objection must apply to interpretations and discussion by the authors, which the editors say they regard as appropriate scientific discourse. “This action taken in response to objections by a manufacturer of a device regulated and approved by FDA is very disturbing,” the editors said.

Schultz emphasized that his intervention was not an effort to please or placate Medtronic. “That is absolutely not the case.” He said his goal is always to be as transparent as possible. “Our goal at the center is to get information out,” Schultz insisted. “I felt there were certain things in terms of the process here that were of concern, and that we as a center needed to take a closer look at; and then there were certain issues related to how this article was put together, how it was vetted, that caused me [to have] concerns.”

Utah Medical Protests FDA Lawsuit

On August 10, 2004, FDA filed a GMP-based complaint for a permanent injunction against Utah Medical Products Inc. (Midvale, UT) in federal court. Soon after, the company's stock price dropped 34%. Shocked by the plunge, company executives complained a week later that FDA failed to discuss its concerns with them. Moreover, they said, the state's elected representatives had “not yet taken an active interest in investigating this situation.” A company board of directors' statement cited U.S. senators Orrin Hatch and Bob Bennett, both Republicans, and Congressman Jim Matheson, a Democrat, as failing to respond to its struggles. The firm's plight comes after three years of wrangling with the agency over repeated findings of GMP/QSR failures.

FDA's complaint for permanent injunction seeks to stop the company from manufacturing and distributing products until it comes into compliance with GMP and QSR requirements. The complaint followed the company's failure to sign a consent decree with FDA that sought the same remedy. In addition, the decree called for the destruction of noncompliant devices and the hiring of an outside consultant to help achieve compliance.

FDA has inspected company facilities four times over the past three years. Its most recent inspection, a month-long affair that ended on March 3, 2004, found the same or similar violations as those cited in previous inspections, according to FDA's complaint.
Included in the list of violations was failure to adequately validate certain manufacturing processes. In addition, failure to implement adequate corrective and preventive action (CAPA) procedures and failure to adequately validate computer software used as part of production or quality control were listed. The inspection also cited the firm for:

• Failures to adequately develop, conduct, control, and monitor production processes to ensure that devices meet specifications.
• Failures to adequately establish and maintain procedures for changing specifications, methods, processes, or procedures.
• Failures to adequately establish, maintain, and document acceptance procedures.
• Failures to adequately establish and maintain controls and procedures to identify valid statistical techniques for the establishment, control, and verification of process capability and product characteristics.
• Failures to adequately establish and maintain adequate CAPA procedures.
• Failures to adequately establish and maintain procedures for the review and evaluation of nonconforming products.
• Failures to adequately establish and maintain procedures for handling complaints.

In the board of directors' statement, Stephen W. Bennett said he found “a complete absence of good-faith dialogue” at the only meeting between Utah Medical Products and FDA. FDA Denver District director Belinda Collins and Southwest Region director Dennis Baker attended the May 3, 2004, meeting.

“[The two agency directors] were not informed, declined to provide any information of substance, and refused to discuss the most recently concluded inspection,” Bennett said in the statement. The company's agenda for the meeting “could not be implemented because information was not exchanged,” he said. Instead, he continued, “the information continued to flow only in one direction,” from his company to FDA.

“I understand that the company's position is unusual, and may appear unwise to some shareholders. I assure you that we haven't been provided another reasonable alternative.”

Outside counsel Larry R. Pilot (McKenna Long & Aldridge) is a former FDA special assistant to the commissioner and associate director of medical device compliance. He has read numerous FDA documents on the case to date. He considers it “a travesty in that the representatives of the agency have refused to dialogue with the company, notwithstanding their leadership's open-door policy.”

Another TMJ Implants Inspection Begins
Another of FDA's Denver District– regulated companies with longstanding FDA problems is TMJ Implants Inc. (Golden, CO). Two FDA bioresearch monitoring investigators in August began what they projected would be a two-week investigation of TMJ's postapproval studies of 224 patients.

The company, which manufactures temporomandibular joint prostheses, has been battling the agency over approval and postmarket reporting issues since 1999. According to CEO Robert W. Christensen, investigators Ted Steinke and William Vitole presented themselves at the company asking to see safety and effectiveness data from prospective studies. The studies have experienced a 34% dropout rate that Christensen attributes to recipient satisfaction with their implants.

The latest inspection followed by 14 days the agency's rejection of an appeal by the company to FDA acting commissioner Lester Crawford. TMJ had requested his intervention in its complaints about a warning letter issued in February, 2004, for 17 alleged MDR nonreporting violations.

The company alleged the agency had no staff expertise to evaluate the “complex” clinical situations in the device explants cited in the warning letter. It contends that none of the failures were attributable to device performance.

AdvaMed Oposes FDA Policy on SUDs

AdvaMed (Washington, DC) said in August that it opposes CDRH's decision to extend for 90 days the validation data submissions deadline for third-party reprocessors of single-use medical devices (SUDs). The extension, which is designed to provide adequate supplemental validation submissions, is required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA).

FDA published its Guidance for Industry and FDA Staff: Medical Device User Fee and Modernization Act of 2002, Validation Data in Premarket Notification Submissions (510[k]s) for Reprocessed Single-Use Medical Devices on June 1, 2004. The guidance calls for manufacturers to have the validation information readily available. Since the reprocessed devices are currently being marketed, such validation data already should have been developed and maintained as part of the quality system regulation requirements.

“The rationale that resulted in this policy statement is no less true today than it was on June 1,” AdvaMed said in comments to FDA.
“Indeed, the fact that to date approximately 20% of the supplemental validation submissions—for products currently on the market—have resulted in ‘Not Substantially Equivalent' findings suggests there is a compelling and urgent need to complete these reviews and make a determination as soon as possible,” the association added.

AdvaMed said it supports a single standard for safety and efficacy for all medical devices. It believes that FDA's decision to allow reprocessors of SUDs additional time to generate data they should already have perpetuates an unfair two-tiered system. Within this system, the association said, there seems to be one standard of safety and effectiveness for OEM devices and a separate, lower standard of safety and effectiveness for reprocessed SUDs.

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